JPS60228423A - Base composition and drug composition for external use - Google Patents

Abstract

PURPOSE:A base composition for external preparations that contains an azulene and a polar compound and medical composition for external use that contains the base composition and drugs, thus showing good skin permeation and high percutaneous absorption. CONSTITUTION:The objective base composition for external use is composed of at least one selected from azulene, camazulene and guaiazulene and of at least one of polar compounds selected from lower alcohols, glycerol, thioglycerols, lactic acid, amides, lactones, ureas and lactams. The amount of the azulene added is 0.1-20wt based on the total of both components. Further, the base composition is combined with a local drug such as local anesthetic, antihistamic or antibiotic or a systemic drug such as diuretic, hypotensor, anti-inflammatory or antiarrhythmic to give a medical composition for external use with high percutaneous absorption.

Description

DETAILED DESCRIPTION OF THE INVENTION [Technical Field] The present invention provides a base composition that enhances the transdermal absorption of a drug;
The present invention relates to an external pharmaceutical composition using the base composition and a method for promoting transdermal absorption of drugs.

[Background of the invention]

Conventionally, when administering drugs to the outer skin, sterilization, disinfection, #i pain,
They were intended to act locally on the outer skin or the subcutaneous tissue, such as antipruritic and antiinflammatory properties.In addition, when systemic effects were intended, oral tablets or injections were traditionally administered. It has been done.

In the case of oral tablets, they have the disadvantage that they are easily subjected to hepatic metabolism after absorption, and that the concentration in the body is higher than necessary in order to maintain the effect.

In addition, some drugs, such as indomethacin, cause gastrointestinal disorders when administered orally.

On the other hand, administration by injection allows rapid absorption, but requires a specialist such as a doctor.

In recent years, transdermal administration methods aiming at systemic effects have been proposed in order to overcome the above-mentioned side effects and drawbacks.

When a drug is administered transdermally, it is easy to maintain the drug;
It has the advantage of being able to control the concentration of the drug in the body, and because it enters the bloodstream through the skin tissue, it is less susceptible to hepatic metabolism.

However, since Masatomi's skin originally has a barrier function that prevents foreign substances from entering the body, the purpose of administering medicines through the skin has been limited to local use. Therefore, when a systemic effect is intended, a transdermal absorption promoting aid is necessary, and various kinds of aids have been proposed in recent years. For example, US Pat. No. 3,551,554 discloses dimethyl sulboquine, dimethyl acetamide, dimethyl formamide, methyl decyl sulfoxide, and the like.

In addition, dimethyl acetamide and ethyl alcohol, isopl
Cobyl alcohol, isopropyl palmitate (U.S. Pat. No. 3,472,431), examples of combinations of 2-pyrrolidone with appropriate oils, straight chain fatty acids and alcohol esters (U.S. Pat. No. 4,017.641), etc. There is, but
When these absorption promoting aids were effective, the following findings were obtained. That is, it has been found that (2) a composition consisting of azulene, cam azulene, or guaiazulene and a specific polar compound increases the skin permeability and percutaneous absorption of a drug.

[Summary of the invention]

The present invention was completed based on the above-mentioned new findings, and its first purpose is to provide a base composition for external preparations that can enhance the skin permeability and percutaneous absorption of drugs.

A second object of the present invention is to provide an external pharmaceutical composition with good skin permeability and transdermal absorption of drugs.

A third object of the present invention is to provide a method for increasing the skin permeability and percutaneous absorption of a drug.

That is, the present invention provides: (1) an external preparation base composition containing at least one kind of azulene and the following specific polar compound; and (2) an external pharmaceutical composition in which a drug is further blended into the above base composition.

Chamomile has been used medicinally since ancient times, and in Europe and America,
It has been used as a home remedy to treat gastrointestinal diseases, colds, eye drops, bath salts, and allergic diseases such as asthma and eczema.

The active ingredient in this chamomile has been confirmed to be guaiasurene, a blue hydrocarbon with a seven-membered ring structure. In addition, it has been confirmed that guaiazulene, which is separated and extracted from camphor indigo oil, has exactly the same pharmacological effects as lijin aszilene. These azulenes are used in various cosmetics, medicines, and external preparations by utilizing their pharmacological effects.

However, it could not be imagined that azulene would promote transdermal absorption of drugs.

The azulene thread compound has the following structure: azulene cam azulene azulene The specific polar compounds used in the present invention are lower alcohol, glycerin, glycerin ester, thioglycerol, lactic acid, lactic acid ester, cyclic urea, general formula [ In the formula, RG, R7 and R8 are each a hydrogen atom and have 1 or more carbon atoms! ) of alkyl (amide compound represented by methyl, ethyl, n-propyl, alkylene glycol, mono- or diethylene glycol, monoalkyl ether of I-l, lactone, general compound (where RI, R2, R3 and R4 are Hydrogen atom, lower alkyl group having 1 to 4 carbon atoms (methyl, ethyl,
n-propyl, iso-butylcopyl, n-butyl, etc.)
, nitro or acyl having 1 to 2 carbon atoms. ] A urea compound represented by General 1 ( 1 [wherein, R5 is a hydrogen atom, lower alkyl having 1 to 3 carbon atoms (methyl, ethyl, n-propyl, iso-propyl, etc.), n is an integer of 3 to 5] It is a lactam compound represented by the following. Examples of such polar compounds are as follows.

■Lower alcohol: Methyl alcohol, ethyl alcohol, n-propyl alcohol, iso-propyl alcohol, n-butyl alcohol, iso-butyl alcohol, SeC-butyl alcohol, L-butyl alcohol, n-amyl alcohol, iSO-amyl alcohol, n-hexyl alcohol, cis-3-hexenol, etc.

(2) Glycerin and its ester: The ester may be mono-, di- or triester, and the acid component is preferably a fatty acid having 2 to 6 carbon atoms, particularly acetic acid. Specifically, glycerin monoacetate, glycerin diacetate, etc. are listed.

(2) Thioglycerol: Any of mono-, di-, or triglycerol may be used. For example, α-monothioglycerol is exemplified.

■Lactic acid, its ester: The Al 1-minor part in the ester has 1 to 4 carbon atoms.
of aliphatic 1 (preferably aliphatic 1-ru. Specifically,
Methyl lactate, ethyl lactate, butyl lactate, etc. are listed.

(2) Cyclic urea: A 5- or 6-membered ring is preferred, and may be substituted with a Cl to 4 alkyl group. Specifically, N, N'-
Dimethyl ethylene urea, ethylene urea, propylene urea, etc. are listed.

■Amide compound (■): Specifically, formamide, N-methylformamide, N,N-dimethylformamide, N. N-diethylformamide, acetamide, N-methylacetamide, N,N-dimethylacetamide, N. N-diethylacetamide, propionamide, N-methylpropionamide, N,N-dimethylpropionamide, N,N-
Diethylpropionamide and the like are listed.

■Alkylene glycol: The alkylene preferably has 2 to 8 carbon atoms,
Specifically, ethylene glycol, 1,3-propanediol, 2-propanediol, butanediol, bentanediol, 2-methyl-2,4-bentanediol, 2-ethyl-1°3-hexanediol, etc. Enumerated.

(2) Monoalkyl ether of mono- or diethylene glycol: The alkyl in the monoalkyl ether preferably has 1 to 2 carbon atoms. Specific examples include ethylene glycol monomethyl ether and ethylene glycol monoethyl ether.

■Lactone: Specific examples include propiolactone, butyrolactone, and β-butyrolactone.

[Co.] Urea compounds (■): Specifically, urea, N-methylurea, N-ethylurea, N
-butylurea, 1.1-dimethylurea, 1.3-dimethylurea, 1.1-diethylurea, 1.3-diethylurea, ], ]I, 3.3-tetramethylurea N-acetyl-
No-methylurea, nitrourea, etc. are listed.

■Lactam compound (■): Specific′. is 2-Mrl lid'・ゞ-methi t''eoli
1 ton, N-methylpiperidone, caprolactam, N
-Methylcaprolactam, etc. are listed.

The azulene compound is blended in an amount of 0.1 to 20% in bundle amount based on the total amount of the polar compound and the azulene compound.

Further, the external pharmaceutical composition of the present invention is prepared by adding a drug to the above-mentioned base composition.

There are no particular restrictions on the drug that can be mixed into the external pharmaceutical composition of the present invention as long as it can be administered to the skin.
Furthermore, if the purpose is to have a systemic effect, the drug will quickly move into the blood.

Specific examples of topical drugs include local anesthetics (e.g., procaine hydrochloride, tetrahydrochloride, dipcaine hydrochloride, lidocaine, lidocaine hydrochloride, piperolyne acetate), anti-scumin agents (e.g., diphenhydramine hydrochloride, chloromaleate), Pheniramine, prompheniramine maleate,
diphenylimidazole, clemizole hydrochloride), antibiotics (e.g., lincomycin, penicillin G1 erythromycin, tetracycline hydrochloride, talindamycin, kanamycin, oxytetracytalline, chloramphenicol, fradiomycin, nyscutin, gramicidin hydrochloride, bacitracin), Antifungal agents [e.g., griseofulvin, N-methyl-N-(3-tolyl)thiocarbamic acid-2-nafthi, 2-reester, cyametazole hydrochloride,
oleothricin, tricumycin, virolnitrile,
5-fluorocytosine].

Specifically, as a systemic drug, benzodiazepine I (
e.g. diazepam, nitrazepam, fludiazepam, lorazepam, prazepam, fludiazepam, clonazebam)
, diuretics [e.g., thiazides (e.g., pendroflumethiazide, polythiazide, methyclothiazide, trichlormethiazide, cyclopenthiazide, hentylhydrochlorotitezide, hydrochlorothiazide, bumetanide), antihypertensive agents (e.g., clonidine), Histamine cheeks [e.g., aminoethers (e.g., diphenhydramine, carbinoxamine, diphenylbilarin), ethylenediamines (e.g.,
fenhenzamine), monoamines (e.g., chlorpheniramine)], non-steroidal anti-inflammatory agents (e.g., indomethacin, ibuprofen, ibufenac, alclofenac, diclofenac, mefenamic acid, flurbiprofen, flufenamic acid, ketoprofen), anti-evil 4
'lItcancer agents [e.g., 5-fluorouracil, ■-(2
-tetrahydrofuryl) -5-fluorouracil, cytarabine, proxuridine], steroidal anti-inflammatory agents (e.g., cortisone, hydrocortisone, prednisolone, prednisone, triamcinolone, dexamethasone, betamethasone), antiepileptic agents (e.g., ethosuximide), antiarrhythmic agents ( e.g., ajmaline, brassimarin, pindolol, propranolol, quinidine), neuropsychiatric agents [
e.g., clofluperolol, trifluperitol, haloperidol, moperon), scopolamines (e.g., methylscopolamine, butylscopolamine), chloropromacine, atropins (e.g., methylatropine bromide, methylanisotropine bromide), blood vessels Extending agents (e.g., isosorbitol cinitrate, nitroglycerin, pentaerythritol tetranitrate, propanyl nitrate, dipyridamole)
, antibiotics [e.g., tetracyclines (e.g., tetracycline, oxytetracycline, methacycline,
Doxycycline, minocycline), chloramphenicols, erythromycins], etc.

The amount of the drug to be mixed should be an amount sufficient to achieve the desired medicinal effect (the amount varies depending on the type of drug, patient's weight, symptoms, etc., and may be selected appropriately according to these conditions.General) Specifically, it is preferably 0.01 to 20% by weight, particularly 0.2 to 10% by weight, based on the total amount of azulene and polar compounds.

Note that the amount of the drug to be used can be adjusted by increasing or decreasing the area of skin and nails attached to the pharmaceutical composition, so it is not necessarily limited to the above-mentioned amount.

The external pharmaceutical composition according to the present invention can be used as it is or with the addition of a known pharmaceutically acceptable third component, and can be used as external preparations such as ointments, plasters, lotions, adhesive tapes, impregnating agents, and gels. administered to Examples of impregnating agents include those prepared by adsorbing the topical pharmaceutical composition or a composition containing a known third component onto a suitable adsorbent (gauze, paperless paper, porous membrane, etc.); It is generally applied to the skin by fixing with adhesive tape.

Examples of the gel agent include those made into a gel using dibenzylidene sorbitol (eg, Gelol DO (manufactured by Shin Nihon Rika Co., Ltd.)) and spread on a support. Examples of bases for adhesive tapes include those known per se, such as acrylic copolymers, polyvinyl ether compounds, rubber and rubber adhesive mixtures. Other external preparations can also be easily prepared by means known per se.

EXAMPLES The present invention will be explained in more detail with reference to Examples and Experimental Examples below, but the present invention is not limited by these in any way.

Examples 1 to 44 Basic formulation (11 drugs 1% by weight (2) Polar compound 74% by weight (3) Azulene 25M% (1), (2) and (3) using those shown in Table 1, respectively) A liquid composition having the above basic formulation was prepared by first mixing (3) with (2) and then dissolving (11).

Control formulation (1) Drug 1% by weight (2) Dimethyl sulfoxide 99% by weight (11 to (2)
).

Comparative examples 1 to 6 +11 drug 1% by weight (2) Polar compound 99% (Prepared by dissolving 11 in (2).

Experimental Example 1 The amount of drug permeation through skin N in the compositions of Examples 17 to 33, the control formulation, and Comparative Examples 1 to 6 was measured using excised rat abdominal skin, and the results are shown in Tables 1 and 2. It was shown to.

Note that the Q values in Tables 1 and 2 mean the following.

(Measurement method) The rat skin was attached to a glass transmission cell so that the part corresponding to the front side of the skin was in contact with the above composition, and the part corresponding to the back side of the skin was in contact with the physiological saline, and the skin was placed in a glass transmission cell so that the composition was in contact with the composition and the part corresponding to the back side of the skin was in contact with the physiological saline. The drug was quantified using high performance liquid chromatography. Note that this experiment was conducted in a sealed container.

Claims (1)

[Claims] +11 At least one azulene compound selected from azulene, cam azulene, and guaiazulene, a lower alcohol, glycerin, glycerin ester, thioglycerol, lactic acid, lactic acid ester, cyclic urea, general formula (wherein, RG, R7 and R8 each represent a hydrogen atom or an alkyl having 1 to 3 carbon atoms. 1, and 1 and 1 each represent a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, nitro, or acyl having 1 to 2 carbon atoms. , lower alkyl having 1 to 3 carbon atoms, and n is an integer of 3 to 5. . (2) The base composition according to claim 11, wherein the amount of the azulene compound is 0.1 to 20% by weight based on the total amount of the azulene compound and the polar compound. (3) Claim No. (11) A pharmaceutical composition for external use containing the composition and a drug. (4) The amount of the azulene compound is 0.1% with respect to the total amount of the azulene compound and the polar compound. The external pharmaceutical composition according to claim (3), characterized in that the amount is 20% by market weight.